Despite meticulous adherence to presently known principles of myocardial protection, ischemia/ reperfusion (I/R) injury, associated with surgically induced myocardial ischemia, secondary to aortic cross clamping, continues to occur following cardiac operations that have been performed in a technically adequate manner. The risk of I/R injury as defined by myocardial contractile dysfunction is significantly greater in patients aged >70 than those <60 years of age and there is evidence to indicate that females have a significantly greater risk potential as compared to males. Our pilot data suggest that anoikis, inflammation and apoptosis are causal mechanisms that significantly increase necrosis in potentially salvageable myocytes and that age is a mitigating risk factor. Our recent and pilot studies indicate that the Jak-STAT signaling pathway is an upstream effector modulating I/R injury and that up-regulation of nuclear STAT1 activation and DMA binding increases anoikis, apoptosis, inflammation and post-ischemic myocardial contractile dysfunction. Our pilot studies also indicate that up-regulation of nuclear STATS activation and DMA binding modulates the deleterious effects of STAT1 activation. Our pilot studies also show that the use of cardioplegia (K/Mg+DZX) provides a means to up-regulate nuclear STATS activation and DMA binding and ameliorate I/R injury, however; the mechanism through which this cardioprotection is afforded in the female and male mature and aged heart is unknown. Our proposed studies utilizing wild type and STAT1 knockout models will allow for the molecular identification of temporal and gender specific signal transduction mechanisms of apoptosis, anoikis and inflammation and their combined and independent contributions to necrosis and post-ischemic contractile dysfunction following surgically induced ischemia and reperfusion. Knowledge of these temporal and gender specific pathways will allow for the development of novel prophylactic interventions allowing for the rescue of salvageable myocytes and enhance myocardial functional recovery following surgically induced ischemia and reperfusion.